ArticleNature communications2025
Effective extracellular payload release and immunomodulatory interactions govern the therapeutic effect of trastuzumab deruxtecan (T-DXd).
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 110 papers, 2 of them syntheses that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
110 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- CDK4/6 inhibitors as conditional immune-priming agents in breast cancer: therapeutic windows, sequencing strategies, and rational combinations with immunotherapy, radiotherapy, and antibody-drug conjugates.Frontiers in immunology · 2026Pooled it
- The efficacy and safety of disitamab vedotin plus immunotherapy in locally advanced or metastatic solid tumors: a systematic review and meta-analysis.Frontiers in immunology · 2026Pooled it
- Neoadjuvant anti-HER2 antibody-drug conjugate SHR-A1811 in Hormone Receptor-positive, HER2-low Breast Cancer: A Phase 2 Clinical Trial (HELEN-015).Nature communications · 2026Trial
- Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer.Nature medicine · 2026Trial
- Mirvetuximab soravtansine plus pembrolizumab in recurrent folate receptor alpha-positive uterine serous carcinoma: a phase II trial.Nature communications · 2026Trial
- Safety and Preliminary Activity of Neoadjuvant Trastuzumab Deruxtecan plus 5-Fluorouracil and Folinic Acid for HER2-Positive, Resectable Esophagogastric Adenocarcinoma: Results from the Safety Run-In Cohort of the Phase Ib/II UCCL-AIO-STO0124-IKF072 NeoART Trial.Oncology research and treatment · 2026Trial
- Extracellular payload release from non-internalizing antibody-drug conjugates: mechanisms and linker technologies.Drug delivery · 2026Review
- Preclinical evaluation of trastuzumab deruxtecan in a new HER2+ leptomeningeal colonization model.Cancer letters · 2026Article
- A modular framework for antibody-drug conjugate biomarkers.Nature reviews. Clinical oncology · 2026Review
- Exploring the immunological effects of antibody-drug conjugates.Nature reviews. Clinical oncology · 2026Review
- Antibody-drug conjugates in breast cancer: redefining targeted therapy.The Journal of clinical investigation · 2026Review
- Antibody-drug conjugate engineering: from design to efficacy and safety.Signal transduction and targeted therapy · 2026Review
- Tumor-on-chip as a personalized platform for rapid drug testing in breast cancer.Cell reports. Medicine · 2026Article
- Intracellular Nanopharmacology of Trastuzumab Deruxtecan Reveals Lysosome-Centered Organelle Vulnerabilities in HER2-Positive Breast Cancer Cells.ACS nano medicine · 2026Article
- Oral toxicities secondary to TROP2 and HER2-directed antibody drug conjugates: a multicenter retrospective cohort study.The oncologist · 2026Article
- Low dose radiotherapy-induced tumor-preferential antigens enhance antibody-drug conjugate efficacy in solid tumors.Neoplasia (New York, N.Y.) · 2026Article
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- Discovery of a Novel Tripeptide Linker that Broadens the Therapeutic Window of Auristatin-Based Antibody-Drug Conjugates by Reducing Bone Marrow Toxicity.Bioconjugate chemistry · 2026Article
- Targeting TROP2 and Exploiting AUNIP as a Determinant of ADC Cytotoxicity and Chemosensitivity in HNSCC and ESCA Cancers.Molecular carcinogenesis · 2026Article
50 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
18 authors.
Funding
Abstract
Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) targeting HER2, exhibiting significant clinical efficacy in breast cancer (BC) with varying HER2 expression, including HER2-low and HER2-ultralow. However, the precise mechanism underlying its efficacy and the contribution of immune activation in these settings remain unclear. Here, we demonstrate that T-DXd efficacy in HER2-low and HER2-negative BC is independent of HER2 engagement and ADC internalization. Instead, its activity relies on extracellular proteases, such as cathepsin L (CTSL), within the tumor microenvironment. Irrespective of their HER2 status, tumor and stromal compartments of invasive BC abundantly express CTSL, which efficiently cleaves the specialized linker of T-DXd, facilitating payload release and inducing cytotoxicity against HER2-low/negative tumors. In HER2-positive BC, the antibody backbone of T-DXd engages Fcγ-receptors and drives antibody-dependent cellular phagocytosis (ADCP). Concurrently, its cytotoxic payload (DXd) induces immunogenic cell death, further activating myeloid cells via TLR4 and STING pathways to enhance tumor antigen presentation to CD8+ T cells. Notably, T-DXd cytotoxicity also upregulates tumor CD47 expression, dampening immune activation. Combining T-DXd with CD47 checkpoint blockade significantly enhances anti-tumor immune responses in a HER2-transgenic BC mouse model, while also inducing durable CD8+ T cell memory to prevent tumor recurrence after therapy cessation.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.